Normal gut microbiota modulates brain development and behavior. Proc Natl Acad Sci USA

Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 02/2011; 108(7):3047-52. DOI: 10.1073/pnas.1010529108
Source: PubMed

ABSTRACT Microbial colonization of mammals is an evolution-driven process that modulate host physiology, many of which are associated with immunity and nutrient intake. Here, we report that colonization by gut microbiota impacts mammalian brain development and subsequent adult behavior. Using measures of motor activity and anxiety-like behavior, we demonstrate that germ free (GF) mice display increased motor activity and reduced anxiety, compared with specific pathogen free (SPF) mice with a normal gut microbiota. This behavioral phenotype is associated with altered expression of genes known to be involved in second messenger pathways and synaptic long-term potentiation in brain regions implicated in motor control and anxiety-like behavior. GF mice exposed to gut microbiota early in life display similar characteristics as SPF mice, including reduced expression of PSD-95 and synaptophysin in the striatum. Hence, our results suggest that the microbial colonization process initiates signaling mechanisms that affect neuronal circuits involved in motor control and anxiety behavior.

    • "Immun. (2015), behavior, suggesting that gut microbes impact anxiety-like behavior (Diaz Heijtz et al., 2011; Neufeld et al., 2011). More recently, the effects of exogenous probiotic microbes, such as bacteria in the genus Bifidobacterium or Lactobacillus, have been shown to attenuate anxiety in both laboratory animals and human participants (Messaoudi et al., 2011a), thus reinforcing the notion that gut microbes can impact behavior. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There are extensive bidirectional interactions between the gut microbiota and the central nervous system (CNS), and studies demonstrate that stressor exposure significantly alters gut microbiota community structure. We tested whether oligosaccharides naturally found in high levels in human milk, which have been reported to impact brain development and enhance the growth of beneficial commensal microbes, would prevent stressor-induced alterations in gut microbial community composition and attenuate stressor-induced anxiety-like behavior. Mice were fed standard laboratory diet, or laboratory diet containing the human milk oligosaccharides 3'Sialyllactose (3'SL) or 6'Sialyllactose (6'SL) for 2weeks prior to being exposed to either a social disruption stressor or a non-stressed control condition. Stressor exposure significantly changed the structure of the colonic mucosa-associated microbiota in control mice, as indicated by changes in beta diversity. The stressor resulted in anxiety-like behavior in both the light/dark preference and open field tests in control mice. This effect was associated with a reduction in immature neurons in the dentate gyrus as indicated by doublecortin (DCX) immunostaining. These effects were not evident in mice fed milk oligosaccharides; stressor exposure did not significantly change microbial community structure in mice fed 3'SL or 6'SL. In addition, 3'SL and 6'SL helped maintain normal behavior on tests of anxiety-like behavior and normal numbers of DCX+ immature neurons. These studies indicate that milk oligosaccharides support normal microbial communities and behavioral responses during stressor exposure, potentially through effects on the gut microbiota-brain axis. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 07/2015; DOI:10.1016/j.bbi.2015.06.025 · 6.13 Impact Factor
  • Source
    • "Recent excitement in the field has been generated from findings implicating the microbial community in a variety of dysbioses from gut associated diseases like obesity and malnutrition (Turnbaugh et al., 2006; Smith et al., 2013), inflammatory bowel disease (Hold, 2014), and celiac disease (Nistal et al., 2012) to neurological disorders like depression (Park et al., 2013), anxiety (Diaz Heijtz et al., 2011), and autism (Hsiao et al., 2013). While significant contributions have been made to understand developed microbial communities in healthy and diseased adults, large gaps remain in understanding the acquisition of the human microbiome at birth, especially among preterm infants (Groer et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: While there has been growing interest in the gut microbiome in recent years, it remains unclear whether closely related species and strains have similar or distinct functional roles and if organisms capable of both aerobic and anaerobic growth do so simultaneously. To investigate these questions, we implemented a high-throughput mass spectrometry-based proteomics approach to identify proteins in fecal samples collected on days of life 13-21 from an infant born at 28 weeks gestation. No prior studies have coupled strain-resolved community metagenomics to proteomics for such a purpose. Sequences were manually curated to resolve the genomes of two strains of Citrobacter that were present during the later stage of colonization. Proteome extracts from fecal samples were processed via a nano-2D-LC-MS/MS and peptides were identified based on information predicted from the genome sequences for the dominant organisms, Serratia and the two Citrobacter strains. These organisms are facultative anaerobes, and proteomic information indicates the utilization of both aerobic and anaerobic metabolisms throughout the time series. This may indicate growth in distinct niches within the gastrointestinal tract. We uncovered differences in the physiology of coexisting Citrobacter strains, including differences in motility and chemotaxis functions. Additionally, for both Citrobacter strains we resolved a community-essential role in vitamin metabolism and a predominant role in propionate production. Finally, in this case study we detected differences between genome abundance and activity levels for the dominant populations. This underlines the value in layering proteomic information over genetic potential.
    Frontiers in Microbiology 07/2015; 6:654. DOI:10.3389/fmicb.2015.00654 · 3.94 Impact Factor
    • "A high rate of turnover may subsequently have an effect on steady-state levels of these neurotransmitters. Turnover of norepinephrine and dopamine specifically may be responsible for the increase in motor activity that is well documented in GF mice (Diaz Heijtz et al., 2011), as these neurotransmitters have roles in increasing blood flow to muscle and central motor control , respectively. While alterations to the population or function of the microbiome may result in differential production of metabolites that enter the periphery, it is unknown if these molecules could cross the BBB and influence neurological function. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Animals share an intimate and life-long partnership with a myriad of resident microbial species, collectively referred to as the microbiota. Symbiotic microbes have been shown to regulate nutrition and metabolism and are critical for the development and function of the immune system. More recently, studies have suggested that gut bacteria can impact neurological outcomes-altering behavior and potentially affecting the onset and/or severity of nervous system disorders. In this review, we highlight emerging evidence that the microbiome extends its influence to the brain via various pathways connecting the gut to the central nervous system. While understanding and appreciation of a gut microbial impact on neurological function is nascent, unraveling gut-microbiome-brain connections holds the promise of transforming the neurosciences and revealing potentially novel etiologies for psychiatric and neurodegenerative disorders. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell host & microbe 05/2015; 17(5):565-576. DOI:10.1016/j.chom.2015.04.011 · 12.19 Impact Factor
Show more